In spite of powerful immunosuppressive drugs the failure rate of organ transplantation is still high. Approximately 20% of kidney grafts fail during the first year, and there is a steady attrition rate thereafter, such that only 20% are predicted to be functional after 20 years. Advances in basic immunology might be usefully applied to transplantation to intervene early and prevent the immunological destruction of allografts. One important immunological mediator that can be targeted for intervention is interferon-gamma (IFN-gamma). IFN-gamma mediates pleiotropic functions in a wide variety of cell types through a specific receptor, the cDNA of which has already been isolated. The human IFN-gamma receptor binds human IFN-gamma with high affinity in a species-specific manner. In addition to this receptor, at least one other species-specific molecule, encoded by a gene(s) on human chromosome 21, is required for signal transduction by human IFN-gamma. The identity of the chromosome 21-encoded signal transducer(s) remains unknown. We propose to identify, isolate and characterize the human chromosome 21-- specific IFN-gamma receptor signal transducer(s). To accomplish this aim we will transfer human genomic DNA or yeast artificial chromosomes containing human chromosome 21 sequences, into a human IFN-gamma receptor expressing murine cell line. Cells which respond to human IFN-gamma with increased murine major histocompatibility complex class I antigen expression will be isolated by fluorescence flow cytometry. The human DNA contained within positive transformants should encode the human IFN-gamma receptor signal transducer(s) and will be used to identify and isolate the cDNA. The identification of this molecule(s) is an essential step towards understanding the multitude of significant effects mediated by IFN-gamma and may lead to the rational design and development of small molecules or interventions which may be clinically useful in preventing kidney graft rejection.